Chemically, repaglinide is S(+)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoic acid having the Formula I,
and is known from U.S. Pat. No. 5,312,924. It belongs to a new class of hypoglycemic benzoic acid derivatives. It offers significantly better biological profile as compared to sulphonylurea class of compounds for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
U.S. Pat. No. 5,312,924 describes a process for the preparation of repaglinide which involves the reaction of (S)-amine of Formula II,
with a carboxylic acid of Formula III,
wherein W represents a (protected) carboxy group or a reactive derivative thereof, and cleaving the protecting group, if necessary, to obtain repaglinide of Formula I.
The reaction of the (S)-amine of Formula II with a carboxylic acid of Formula III is carried out in the presence of N,N′-carbonyldimidazole, N,N′-dicyclohexylcarbodiimide or triphenylphosphine/carbon tetrachloride and triethylanmine. N,N′-carbonyldimidazole is expensive and gives low yields (50 to 55%) while the use of triphenylphosphine/carbon tetrachloride necessitates chromatographic purification to obtain repaglinide of desired purity. The use of N,N′-dicyclohexylcarbodiimide generates dicyclohexyl urea as a by-product which can only be removed by repeated crystallizations of the product resulting in increased cycle time and the cost of production. Furthermore, the N,N′-dicyclohexylcarbodiimide is toxic and its use on a commercial scale is undersirable.
Several variations of this method are known which involve the condensation of differently substituted amines and carboxylic acids, followed by suitable chemical modification of the substituents to obtain repaglinide. All of these variations involve additional number of synthetic steps and are therefore not suitable for commercial scale production of repaglinide.
It is, therefore desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of repaglinide which process improves the economics by employing less expensive and less hazardous raw materials and is more productive. The process avoids the tedious and cumbersome procedures of chromatography or special recrystallization techniques, is economical and convenient to operate on a commercial scale.
The present invention provides a process for the preparation of repaglinide of Formula I comprising:
a) reacting the (S)-amine of Formula II with a protected carboxylic acid of Formula IV,
                wherein R is a protecting group, in the presence of pivaloyl chloride and a base, and        
b) removing the protecting group to obtain repaglinide.
The protecting group R in the compound of Formula IV is any carboxylic acid protecting group which is easily removed, such as methyl, ethyl, tert.-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, and the like.
The reaction is carried out in the presence of a suitable base which may be either organic or inorganic. Examples of suitable organic bases include amines such as diisopropylamine, dicyclohexylamine, 1,8-diazabicyclo[5.4.0] undec-7-ene, triethylamine, tributylamine, N,N-dimethylaniline, diisopropylethylamine, and the like. Suitable inorganic bases include potassium carbonate, sodium carbonate, and the like.
The reaction may be carried out in a suitable solvent such as dichloromethane, toluene, xylene, and the like. The reaction is carried out at temperatures of between −25° C. and 40° C., but preferably at temperatures of between −10 and 25° C.
The removal of a carboxylic acid protecting group is achieved by suitable methods known in the art such as acidic or basic hydrolysis or hydrogenolysis.